Inflammation refers to a condition in which a series of complex physiological reactions such as activation of enzymes by various inflammatory mediators and immune cells, secretion of inflammatory mediators, body fluid infiltration, cell migration, tissue destruction, and the like occur when tissues are stimulated by damage or exogenous sources of infection, such as bacteria, fungi, viruses, etc., and thus is accompanied with symptoms such as erythema, edema, pyrexia, pain, etc.
As described above, an in vivo defense response for restoring the structure and function of the tissues damaged by infection, trauma, etc. is generally referred to as an inflammatory response.
Migration of white blood cells into a site of inflammation is important for providing a swift solution to the infection and recovering from tissue damage caused by various traumas. However, an excessive or prolonged inflammatory response, which may be caused by unremoved exogenous sources of infection or endogenous substances, leads to damaged human tissues, and diseases as cancer, inflammatory skin disease, arthritis, etc.
The inflammatory diseases are classified into acute and chronic inflammatory diseases whose symptoms or pathological features are distinguishable. Local symptoms of acute inflammation such as allergies or bacterial and viral infections appear as changes in blood flow and blood vessel size, a change in vasopermeability, and leukocytic infiltration.
On the other hand, main pathological features of chronic inflammation, including rheumatoid arthritis, atherosclerosis, chronic nephritis, liver cirrhosis, etc., include prolonged infiltration of monocytes, neutrophils, lymphocytes, and plasma cells into sites of inflammation because inflammation inducers are not removed, leading to chronic inflammatory responses.
Various factors are associated with the inflammatory response in inflammatory diseases. Specifically, inflammatory mediators expressed in the site of inflammation include cytokines, chemokines, reactive oxygen intermediates, cycloxygenase-2 (COX-2), 5-lipoxygenase (5-LOX), matrix metalloproteinase (MMP), etc., and play an important role in occurrence and maintenance of the inflammatory response.
It has been known that expression of such inflammatory mediators is regulated by transcription factors, such as nuclear factor κB (NF-κB), signal transducer and activator of transcription 3 (STAT3), activator protein 1 (AP-1), hypoxia-inducible factor 1a (HIF-1a), etc.
For example, the present inventors have proposed that 2,4-bis(p-hydroxyphenyl)-2-butenal induces inactivation of NF-κB, and thus may be used as a medicine having an anti-inflammatory or anti-arthritic effect, as disclosed in Korean Unexamined Patent Publication No. 2012-0094308.
Also, Korean Unexamined Patent Publication No. 2014-0093435 discloses that chlorogenic acid derivatives suppress excessive nitric oxide generation, and thus may be used as therapeutic agents against inflammatory diseases, which have an effective anti-inflammatory activity.
Meanwhile, in addition to NF-κB, STAT3 is also an important transcription factor associated with inflammatory and immune responses.
As a representative inflammatory disease, arthritis can be treated and prevented by inhibiting the activity of STAT3.
Arthritis is a representative cartilage-related disorder that is generally referred to as a condition by what causes an inflammatory change occurring in the joints, and refers to a condition caused by the loss of cartilage serving to connect two bones so that the bones move smoothly.
Arthritis is divided into various types of arthritis such as degenerative arthritis or osteoarthritis, rheumatoid arthritis, avascular necrosis of the femoral head, traumatic arthritis, tuberculosis arthritis, and pyogenic arthritis. Currently, there are approximately one million arthritis patients in Korea. Here, women outnumber men two to one. In this case, arthritis is most often observed in climacteric women.
Among these, osteoarthritis (degenerative arthritis) is a type of arthritis that develops due to a degenerative change in cartilage and its surrounding bones among various components constituting the joint, that is, a joint disease which is generally severely painful in the joints under full body weight, that is, knee joints, hip joints, etc., makes it hard to move, and may lead to joint deformation when left untreated.
Osteoarthritis is a representative degenerative disease that is closely associated with aging and from which approximately 10 to 15% of the total population suffers. In particular, approximately 60 to 80% of the elderly population aged 65 or older suffers from osteoarthritis. The causes of osteoarthritis are deeply associated with senility or excess weight, and osteoarthritis develops more often and severely in women with age. Initial symptoms of osteoarthritis involve a throbbing pain in one or two joints with stiffness, and may lead to joint deformation when left untreated for a long time.
The therapeutic effects on arthritis associated with STAT3 are disclosed in various documents [Jun-Geol Ryu et al., Treatment of IL-21R-Fc control autoimmune arthritis via suppression of STAT3 signal pathway mediated regulation of the Th17/Treg balance and plasma B cells, Immunol. Lett. 2015, 163(2), 143-150; Boyle D L et al., The JAK inhibitor tofacitinib suppresses synovial JAK1-STAT signaling in rheumatoid arthritis, Ann Rheum Dis. 2014 Nov. 14; JooYeon Jhun et al., Red ginseng extract ameliorates autoimmune arthritis via regulation of STAT3 pathway, Th17/Treg balance, and osteoclastogenesis in mice and human, Mediators Inflamm. 2014; 2014:351856; Seon-Yeong Lee et al., Interleukin-17 increases the expression of Toll-like receptor 3 via the STAT3 pathway in rheumatoid arthritis fibroblast-like synoviocytes, Immunology. 141(3), 353-361; Jin-Sil Park et al., JAK2-STAT3 blockade by AG490 suppresses autoimmune arthritis in mice via reciprocal regulation of regulatory T Cells and Th17 cells, J. Immunol. 2014, 192(9), 4417-4424; Eun-Ji Yang et al., EGCG attenuates autoimmune arthritis by inhibition of STAT3 and HIF-1α with Th17/Treg control. PLoS One. 2014, 9(2), e86062].
Typical methods of treating arthritis known in the art include drug therapies using painkillers, steroids, non-steroidal anti-inflammatory agents, etc., or using chondroprotective agents such as glucosamine, chondroitin, etc., surgical treatments such as artificial joint replacement surgery, etc. The drug therapies serve to non-specifically alleviate pain or reduce the inflammatory response itself, and the chondroprotective agents serve to minimize the loss of function of the joint by supplying nutrients to chondrocytes or reducing the impact on the joint. However, the therapy using drugs has a significant purpose of alleviating pain, but may have severe side effects caused by the use of drugs, such as dysfunction of various organs, depression, bacterial infections, etc.
Therefore, there is a need for sustainable development of effective methods of treating arthritis, which have few side effects but high safety. Also, as the aging of population proceeds rapidly with the recent entrance into an aging society, the market for arthritis therapeutic agents tends to constantly grow.
In the case of the arthritis therapeutic agents, research on new drug development has mainly featured the development of biological preparations so far. However, after a TNF-α inhibitor has been developed based on the mechanism of pathogenesis, remarkably high sales were achieved within a short period of time and a significant added value was created due to the breakthrough therapeutic effects.
For example, Korean Registered Patent No. 10-1126164 discloses that an essential oil extracted from Curcuma wenyujin is used as an active ingredient, has an anti-inflammatory activity because it serves to suppress TNF-α production, and may be used for compositions for preventing and treating inflammatory diseases such as arthritis.
Also, Korean Registered Patent No. 10-1201549 discloses that a pharmaceutical composition contains an extract of Eucommia ulmoides as an active ingredient, and thus may be used as a therapeutic agent for rheumatoid arthritis, which has an anti-inflammatory activity and an inhibitory effect on osteoclasts.
These patents exhibit high stability when administered as herbal preparations, but it is difficult to expect a fundamental therapeutic effect against arthritis.